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Fennel (Foeniculum vulgare)

fennel_mainFennel is an edible flowering plant that is related to the carrot. In the UK it is normally encountered in two distinct forms: as fennel seeds, a spice which is used in eastern cookery, and as a swollen bulb which is used as a vegetable. Formally, the latter is a cultivar known as Florence Fennel. Both the seeds (which in reality are the fruit of the plant, not its seeds) and the bulb taste similar to aniseed. The essential oils of this plant make for a fragrant tea, while one of its key molecules is useful in chemical synthesis.

Figure 1: Prometheus carrying fire in a fennel stalk.

1) The main image shows sliced fennel bulb and dried fennel seeds, along with three key molecules found in both (clockwise from top right): estragole, E-anethole and (+)-fenchone. [We are not fully back in labs, so photos from the kitchen…]

Though native to the Mediterranean, fennel has spread all over the world. In ancient Greek mythology, Prometheus stole fire from the Gods on Mount Olympus using a fennel stalk, and used it to create civilisation for mankind. The first manmade chemical element, artificially created in a nuclear reactor, was named Promethium because its creators felt that they, too, might be stealing from the Gods for the benefit of humanity.

Fennel has long been used in folk medicine. It is reputed to be carminative – that is, it reduces wind – and has been used to treat colicky babies. This has been scientifically tested, with limited but not discouraging results. Similarly, trials have shown fennel oil to be useful in relieving the symptoms of irritable bowel syndrome. (J. Gastrointestin. Liver Dis., 2016, 25, 151-157; Ann. Gastroenterol., 2018, 31, 685–691). It is also traditionally used as a galactologue – that is, to stimulate milk production in breastfeeding mothers. There is little scientific evidence for the effectiveness of this, though there is evidence that taking too much can have adverse effects on both mother and child.

2) The chemical primarily responsible for the taste and smell of fennel is called anethole; it also found in other similarly tasting things like aniseed and liquorice. Anethole is an alkene – that is, it has a carbon-carbon double bond – and it exists as two different isomers, known as E-anethole and Z-anethole. We have noted before that nature is often very good at synthesising only one isomer when a range are possible, and E-anethole (with the hydrogen atoms on opposite sides of the double bond) is the one found in fennel. A second chemical found in fennel is called estragole (also known as methyl chavicol), and this is another isomer of anethole. Here the double bond has moved to the end of the chain, so estragole is a structural isomer of anethole – it has the same molecular formula, but the atoms are arranged differently.

Figure 2: The chemicals mainly responsible for the taste of fennel.

A third compound responsible for the taste of fennel is called fenchone, which is a ketone because it has a carbon-oxygen double bond. Fenchone also has isomers, which in this case are mirror images of each other – they are enantiomers. They both smell the same (Chemical Senses, 1999, 24, 161–170) – that is, a bit like camphor – but only (+)-fenchone is found in fennel; its enantiomer, (-)-fenchone, is found in wormwood and tansy (Flavour Fragr. J., 1992, 7, 169-172). The relative amounts of fenchone, anethole and estragole vary in different parts of the fennel plant and at different times of the year (J. Essent. Oil Res., 2000, 12, 159-162), and under different growing conditions (Biochem. Sys. Ecol., 2009, 37, 308-316).

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Fennel bulb

These organic compounds can be extracted by a process called steam distillation, which generates the essential oil of fennel. If a mixture of water and fennel (either green matter or seeds) is boiled, then the steam generated is a mixture of water vapour and these organic compounds. If the steam is condensed and collected, it will separate into two layers (just like oil and water), which can be separated. A peculiarity of the process is the fact that it occurs at a temperature below the boiling point of water, even though anethole boils at 234 °C. This means it can be isolated without heating to very high temperatures, which tend to make it decompose, and this is the process by which many essential oils besides fennel are collected; for example, it is used for lavender and cloves.

3) There’s a classic undergraduate chemistry experiment which demonstrates the dehydration of methylcyclohexanol (J. Chem. Educ., 1967, 44, 620). It involves generating a carbocation and then taking the two electrons from a neighbouring carbon-hydrogen bond to quench it, in the process eliminating a proton and generating a double bond – this is called an E1 elimination reaction. That reaction is analogous to the way that pinene is biosynthesised, as shown in Figure 3 below.

What has this got to do with the chemistry of fennel? Well, the core of the fenchone molecule is also synthesised from the pinyl cation, but via a different mechanism in which the positive charge reacts with the two electrons of a neighbouring carbon-carbon bond. Taking those two electrons breaks the carbon-carbon bond where they were, but generates a new one where the positive charge had been. Formally, this is a 1,2-carbocation rearrangement, known as a Wagner-Meerwein rearrangement (J. Chem. Educ., 2000, 77, 858).

Figure 3: The ways in which various carbocations react. (a) is the experiment our undergraduates do, and is analagous to (b), the biosynthesis of pinene. However, in (c) a different pair of electrons are used – a Wagner-Meerwein rearrangement – which ends up as fenchone.

fenchone3d

Figure 4: The 3D structure of fenchone.

Although we always draw them as hexagons, we shouldn’t forget that fenchone (and all the other terpenes) are not flat. A six-membered cyclohexane ring is puckered, and in fenchone, the bridge across bends it even more. The 3D structure shown in Figure 4 (Acta Cryst., 2001, E57, o1034-o1035) demonstrates this, and shows how the oxygen atom (red) is surrounded by methyl groups.

This means that the reactivity of the carbonyl group is rather different to most ketones. Reaction of fenchone with many Grignard reagents simply returns fenchone, though tests indicate that the Grignard has reacted (Charles S Sell, A Fragrant Introduction to Terpenoid Chemistry). In itself this is not unusual; hindered ketones often react with Grignards to produce enolates, which are hydrolysed back to the ketone during workup. Because the Grignard reagent cannot get at the carbonyl, it abstracts a proton from the α-carbon atom instead. However, fenchone does not have any α-protons, so a proton is lost from a β-carbon atom instead, creating a transannular carbon-carbon bond (Figure 5). This is only possible because the conformation of the 6-membered ring puts the particpating atoms in close proximity and in the correct orientation.

Figure 5: Sterically hindered ketones will react with Grignard reagents to make an enolate (top); on aqueous workup, the ketone is regenerated. Fenchone does this in an unusual manner (bottom).

The steric protection afforded the fenchone carbonyl group has led to it being exploited in organic synthesis. Oxaziridines, which are compounds with a triangular C-O-N ring are generally quite unstable, but if they’re made from fenchone then this is not the case, because the methyls offer protection (J. Org. Chem., 2000, 65, 4204-4207). These oxaziridines can then be put to use as synthetic reagents (Nat. Chem., 2017, 9, 681–688). Metal-aryl complexes such as Grignard reagents and aryllithiums are very basic, which means that attempts to add -NH (aminate) or -OH (hydroxylate) to them normally just result in transferring H instead. However, oxaziridines derived from fenchone (and also camphor) will transfer NH groups to the aryl fragment, creating a useful new method of amination. This is because shielding the NH group reduces its acidity, allowing it to be transferred whole (Figure 6).

Figure 6: An aryl Grignard reagent will react with a fenchone-protected oxaziridine in an amination reaction.

So now you know that the next time you’re having a nice calming cup of fennel tea, the steam coming off it isn’t just water vapour. Collect it, and make your own essential oil – you might need more than a cupful of tea, though.

Contributors: Chris Adams (Research & Writing), Natalie Fey (Main Image)

Picture credits: Figure 1 is “Prometheus Brings Fire to Mankind” by Heinrich Fueger (1817), via wikimedia commons.